The present invention relates to a pharmaceutical preparation useful in controlled ovarian hyperstimulation (COH) as well as to a method to prevent a premature LH surge.
The glycoprotein hormones Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) are released from the pituitary gland under control of Gonadotropin Releasing Hormone (GnRH). They act on the ovary to stimulate steroid synthesis and secretion and thus play a central role in the reproductive cycle.
In the normal cycle, there is a mid-cycle surge in LH concentration which is followed by ovulation. The LH surge is a consequence of the raise in estrogen levels brought about by the endogenous secretion of LH and FSH. The estrogen is part of a positive feedback mechanism resulting in the elevated LH level.
GnRH analogues are useful for a variety of disorders in which immediate reversible suppression of the pituitary-gonadal axis is desired. This can in principle be achieved with GnRH agonists as well as with GnRH antagonists. In comparison to GnRH agonists, GnRH antagonists have the advantage of not inducing an initial release of gonadotropins (flare-up) and steroids before suppression.
Currently, GnRH agonists are clinically applied for the prevention of endogenous LH-surges during controlled ovarian hyperstimulation for Assisted Reproduction Techniques (ART). Specific disadvantages of GnRH agonists are the initial flare-up and the rather long period until pituitary suppression becomes effective. Usually, patients undergoing COH start only treatment with (recombinant) FSH after 2 to 3 weeks pretreatment with GnRH agonists.
Women treated for this purpose without GnRH analogues, all show attenuated LH rises irrespective of the treatment schedule used. Usually these rises occur prematurely due to a positive feedback of rising estradiol (E2) produced by a cohort of relative small follicles. The exposure of non-mature follicles to high levels of LH leads to premature luteinisation of granulosa cells and hence to increased production of progesterone and decreased synthesis of E2. These changes lead to disrupted maturation and decreased fertilization and implantation rates. Success rates of COH cycles in which premature LH rises are detected, are reported to be low and often these cycles are canceled because the number and/or size of follicles is still too small.
The suppressive potency of GnRH agonist treatment in women with normal menstrual cycles may depend on structure-receptor interaction, elimination half-life dosage and route of administration of the specific GnRH agonist applied. Clinical studies with different regimens of GnRH agonists have clearly demonstrated that the amount of remaining LH in women undergoing COH is always sufficient to support folliculogenesis and estrogen biosynthesis induced by pure FSH. In these studies the minimum amount of circulating endogenous LH was only 1 to 2 IU/L. In some women LH concentrations dropped below 0.5 IU/L but still FSH treatment appeared to be effective.
In contrast to GnRH agonists, GnRH antagonists by GnRH receptor competition provide an immediate inhibition of gonadotropin secretion, especially of LH. Thus, during COH by FSH, GnRH antagonist treatment is only required during the few days when there is an increased risk for a premature LH surge.
The present invention relates to the use of the antagonist ganirelix which has the following chemical name:
N-Acetyl-3-(2-naphtyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-L-tyrosyl-Nxcfx89,Nxcfx89-diethyl-D-homoarginyl-L-leucin-Nxcfx89,Nxcfx89-diethyl-Lhomoarginyl-L-propyl-D-alanylamide acetate. The abbreviated structure is (N-Ac-D-Nal(2)1,D-pClPhe2D-Pal(3)3,D-hArg(Et2)6,L-hArg(Et2)8,D-Ala10)-GnRH.
In a phase I study, published by Nelson et al., 1995, rapid, profound, reversible suppression of the pituitary-gonadal axis was obtained in reproductive age women. In this study women started on days 6 to 9 of the menstrual cycle with a daily SC injection of 1 mg or 2 mg of GnRH ganirelix for 8 consecutive days. Nelson et al demonstrated that maximal mean LH suppression was approximately 60% at 8 h after the first injection and that at that time point LH levels were 4 to 5 IU/L. During the treatment period, serum LH measured just prior to the following administration of ganirelix remained at steady state (5 to 6 IU/L) at a dose of 2 mg ganirelix whereas those treated with 1 mg ganirelix showed slowly increasing concentrations of endogenous LH (from 6 to 9 IU/L)
The GnRH antagonist ganirelix is disclosed in U.S. Pat. No. 4,801,577 for nonapeptide and decapeptide analogs of LHRH useful as LHRH antagonists. This patent, which is fully incorporated herein by reference, describes the method for the preparation of these compounds. It is indicated that the compounds described therein can be used for the prevention of ovarian hyperstimulation. For human therapy a daily range is suggested for administration of the active ingredient between 0.001 and 5 mg/kg body weight, preferably between 0.01 and 1 mg/kg.
Surprisingly, however, clinical experiments have indicated that the dosage range is very narrow and that a deviation from this range is either leading to premature LH rises or to too much suppression of endogenous LH and as a consequence of estrogen biosynthesis. Accordingly, the implantation rate is unacceptable low. In contrast, a daily dose between 0.125 mg and 1 mg of ganirelix per subject on one hand prevents premature LH rises to occur and at the same time maintains sufficient LH to support follicular maturation and estrogen biosynthesis, both required to ensure successful treatment outcome.